Crystalline forms of dimethoxy docetaxel and methods for preparing the same

ABSTRACT

The invention relates to anhydrides, solvates and ethanol hetero-solvates and hydrates of dimethoxy docetaxel or (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β, 10β-dimethoxy-9-oxo-tax-11-ene-13α-yle, and to the preparation thereof.

This application is a divisional of U.S. patent application Ser. No.14/453,087, filed Aug. 6, 2014, which is a divisional of U.S. patentapplication Ser. No. 13/767,966, filed Feb. 15, 2013, now U.S. Pat. No.8,846,959, which is a divisional application of U.S. patent applicationSer. No. 12/837,559, filed Jul. 16, 2010, now U.S. Pat. No. 8,378,128,which is a continuation of International Patent ApplicationPCT/FR2009/000042 filed Jan. 15, 2009, all of which are incorporatedherein by reference; and which claim priority to French PatentApplication No. 0800243 filed on Jan. 17, 2008.

The present invention relates to crystalline forms of dimethoxydocetaxel or 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and tomethods for the preparation thereof.

BACKGROUND OF THE INVENTION

4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxy carb onylamino-2-hydroxy-3-phenylpropionate exhibits notable anticancer andantileukaemic properties.

4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate isprepared according to the method which is described more particularly inPCT International Application WO96/30355 or PCT InternationalApplication WO99/25704. According to the method described in theseapplications, the product is not crystallized and is not characterized.

It was found that the acetone solvate of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (calledform A) was completely determined and characterized according to thepatent published under number WO2005/028462.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to new crystalline forms, with theexclusion of the acetonate form, the only one known to date.

According to the present invention, it has now been found that certainanhydrous forms, certain ethanolic solvates or heterosolvates andhydrated forms have been completely characterized from a physical andchemical structure point of view.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a Differential Scanning calorimetry (DSC) analysis foranhydrous form D.

FIG. 2 depicts a Powder X-Ray Diffraction (PXRD) analysis for anhydrousform D.

FIG. 3 depicts Fourier Transform InfraRed (FTIR) spectrometry analysisfor anhydrous form D.

FIG. 4 depicts a Powder X-Ray Diffraction (PXRD) analysis for ethanolateform D.

FIG. 5 depicts a Powder X-Ray Diffraction (PXRD) analysis for ethanolateform E.

DETAILED DESCRIPTION OF THE INVENTION

According to the invention, among the anhydrous forms of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate,five different forms have been identified, among the ethanolic solvatesor heterosolvates of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate,four different forms have been identified and among the hydrates of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, twodifferent forms have been identified.

The five anhydrous forms identified were obtained according to thefollowing methods:

-   -   The anhydrous form B by a method which consists in heating the        acetone form or form A obtained according to the patent        mentioned above, between 100 and 110° C. under vacuum or        nitrogen sweeping. This treatment is preferably carried out for        at least 9 hours before a return to ambient temperature without        inducing chemical decomposition. Its melting point by DSC is        approximately 150° C. The PXRD diagram of the anhydrous form B        exhibits characteristic lines located at 7.3, 8.1, 9.8, 10.4,        11.1, 12.7, 13.1, 14.3, 15.4 and 15.9±0.2 degrees 2-theta.    -   The anhydrous form C is obtained by maturation of the acetone        solvate form A, or of the anhydrous form B, in water followed by        drying at up to 50° C. and maintaining between 0 and 5% RH at        ambient temperature. Its melting point by DSC is approximately        146° C. The PXRD diagram of the anhydrous form C exhibits        characteristic lines located at 4.3, 6.8, 7.4, 8.7, 10.1, 11.1,        11.9, 12.3, 12.6 and 13.1±0.2 degrees 2-theta. It is, among the        various anhydrous forms, the least stable of all the forms        described in the present invention. In the presence of a        relative humidity of greater than 5%, it changes to a hydrated        form.    -   The anhydrous form D is obtained according to a first method by        crystallization of the form A in an oil (especially Miglyol),        following by rinsing with an alkane, for example heptane; the        second preparation method consists in leaving a solution of        4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl        (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate        in a mixture of Polysorbate 80, pH 3.5, ethanol and water        (preferably a 25/25/50 mixture) to crystallize for approximately        48 hours. Its boiling point by DSC is approximately 175° C. (cf.        FIG. 1) and is found to be the highest of all the anhydrous        forms isolated. The PXRD diagram of the anhydrous form D (cf.        FIG. 2) exhibits characteristic lines located at 3.9, 7.7, 7.8,        7.9, 8.6, 9.7, 10.6, 10.8, 11.1 and 12.3±0.2 degrees 2-theta.        The FTIR spectrum of the anhydrous form D exhibits        characteristic bands located at 979, 1072, 1096, 1249, 1488,        1716, 1747, 3436±1 cm⁻¹(cf. FIG. 3). Among all the forms        described in the present invention, it is the most stable        anhydrous form.    -   The anhydrous form E is obtained at ambient temperature by        maturation of the acetone form or form A in ethanol so as to        intermediately form an ethanolic form which is subsequently        desolvated under nitrogen sweeping or by heating at        approximately 100° C. for 2 hours. Its melting point by DSC is        approximately 157° C. The PXRD diagram of the anhydrous form E        exhibits characteristic lines located at 7.1, 8.1, 8.9, 10.2,        10.8, 12.5, 12.7, 13.2, 13.4 and 13.9±0.2 degrees 2-theta.    -   The anhydrous form F is obtained by desolvating the        ethanol/water heterosolvate at 120° C. under a nitrogen        atmosphere for 24 hours and then maintaining in a dry        environment at 0% RH at ambient temperature. Its melting point        by DSC is approximately 148° C. The PXRD diagram of the        anhydrous form F exhibits characteristic lines located at 4.4,        7.2, 8.2, 8.8, 9.6, 10.2, 10.9, 11.2, 12.1 and 12.3±0.2 degrees        2-theta.

There are four crystalline forms identified in ethanolic solvate orheterosolvate form:

-   -   The ethanolate form B is obtained at ambient temperature by        maintaining the anhydrous form B in an ethanol-vapour-saturated        environment. The PXRD diagram of the ethanolate form B exhibits        characteristic lines located at 7.3, 7.8, 8.8, 10.2, 12.6, 12.9,        13.4, 14.2, 14.7 and 15.1±0.2 degrees 2-theta.    -   The ethanolate form D is obtained at ambient temperature by        maintaining the anhydrous form D in an ethanol-vapour-saturated        environment. The PXRD diagram of the ethanolate form D (cf.        FIG. 4) exhibits characteristic lines located at 3.8, 7.5, 7.7,        8.4, 9.4, 10.3, 10.5, 11.1, 11.5 and 11.9±0.2 degrees 2-theta.    -   The ethanolate form E is obtained at ambient temperature by        maturation of the acetonate form A in ethanol. The PXRD diagram        of the ethanolate form E (cf. FIG. 5) exhibits characteristic        lines located at 7.1, 8.1, 8.8, 10.2, 10.7, 12.5, 13.2, 13.4,        13.9 and 14.2±0.2 degrees 2-theta.    -   The ethanol/water heterosolvate form F is obtained by        maintaining the form B in a minimum amount of ethanol at reflux,        slow cooling and isolation at ambient temperature and ambient        relative humidity. The PXRD diagram of the ethanol/water        heterosolvate form F exhibits characteristic lines located at        4.4, 7.2, 8.2, 8.3, 8.8, 9.6, 10.3, 10.9, 11.2 and 12.2±0.2        degrees 2-theta.

There are two crystalline forms identified in hydrate form:

-   -   The monohydrated forms C are obtained at ambient temperature by        maintaining the anhydrous form C in an atmosphere containing at        least 10% relative humidity. The PXRD diagram of the monohydrate        form C exhibits characteristic lines located at 4.3, 6.8, 7.4,        8.6, 10.1, 11.1, 11.9, 12.2, 12.6 and 13.3±0.2 degrees 2-theta.    -   The dihydrate form C is obtained at ambient temperature by        maintaining the anhydrous form C in an atmosphere containing at        least 60% relative humidity. The PXRD diagram of the dihydrate        form C exhibits characteristic lines located at 4.2, 6.9, 7.5,        8.4, 9.9, 10.9, 11.7, 12.3, 12.6 and 13.2±0.2 degrees 2-theta.

Other, nonethanolic, solvates of the form B were prepared, such as inparticular those obtained with the following solvents: dichloromethane,diisopropyl ether, n-propanol, isopropanol, toluene, methyl isobutylketone, tetrahydrofuran, dimethylformamide, ethyl acetate, etc.

The present invention will be described more fully by means of thefollowing examples which should not be considered to limit theinvention.

Experimental analysis conditions:

Differential Scanning Calorimetry (DSC):

The measurements were carried out on a T.A. Instruments DSC2010 thermalanalyser. The sample is subjected to temperature programming from 25° C.to 225° C. with a heating rate of 5° C/min. The product is placed in acrimped aluminium capsule and the amount of product analysed is between2 and 5 mg. Constant nitrogen sweeping at 55 mL/min is used in the ovenchamber.

Powder X-Ray Diffraction (PXRD):

The analyses were carried out on a Panalytical X′Pert Pro diffractometerwith a reflection-mode Bragg-Brentano focusing geometry (θ-2θ) assembly.The product analysed is deposited as a thin layer on a silicon singlecrystal. A copper anticathode tube (45 kV/40 mA) supplies an incidentradiation Cu Kα₁ (λ=1.5406 Å). The beam is collimated using Sollersslits which improve the parallelism and variable slits which limitscattering. An X′Celerator detector completes the device. The diagramrecording characteristics are the following: sweeping from 2 to 30degrees 2θ, counting time from 100 to 500 seconds per step with a stepof 0.017°.

Fourier Transform InfraRed (FTIR) spectrometry:

The solid samples were analysed using a Nicolet Nexus spectrometer. Theanalysis is carried out by attenuated total reflectance (ATR) using aSmart Orbit accessory from the company Thermo (single reflection diamondcrystal ATR accessory). The spectral range swept is between 4000 and 400cm⁻¹ with a resolution of 2 cm⁻¹ and an accumulated scan number of 20.

EXAMPLE 1

Two tests of dissolution of approximately 550 mg of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in 14 gof Miglyol 812 Neutral oil, Sasol are carried out. Magnetic stirring iscarried out at 500 rpm for 24 hours at ambient temperature.

After one week, the samples are vacuum-filtered and rinsed with heptane.Each sample is analysed by PXRD for confirmation of the form obtained.After filtration, between 300 and 350 mg of anhydrous form D areobtained.

EXAMPLE 2

Approximately 3 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate aredissolved in a mixture of 50 mL ethanol+50 mL Polysorbate 80, pH 3.5.100 mL of water are added to the previous mixture and the whole ishomogenized. After storage for 48 hours at ambient temperature, crystalsof anhydrous form D appeared. The amount of crystallized productrecovered by filtration is approximately 2.45 g.

A comparative stability study was carried out between the acetonesolvate form A and the anhydrous form D. The comparison of the PXRDanalyses carried out on the A and D forms immediately after productionand after having maintained said forms at 40° C. for one month gives thefollowing results:

-   -   Form A: partial desolvation resulting in a mixture of the        acetone solvate form A and of the anhydrous form B being        obtained.    -   Form D: no change detected after maintaining at 40° C. for one        month.

What is claimed is:
 1. Anhydrous form F of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate,characterized by a PXRD diagram exhibiting characteristic lines locatedat 4.4, 7.2, 8.2, 8.8, 9.6, 10.2, 10.9, 11.2, 12.1 and 12.3±0.2 degrees2-theta.